In the post Cold War setting, a number of potential scenarios involving radiation exposure of humans is likely to result from a variety of diverse events—such as a limited nuclear exchange, a terrorist action using an improvised nuclear device, an accidental or intentional nuclear power plant release, or even a conventional explosive employed as a means for disseminating radioactive materials (Radiation Dispersal Device). In such scenarios, radioactive contamination may vary widely. Consequently, the exposure of individuals cannot be calculated and must be measured in the individual for an accurate assessment of risk.
Clearly, there are plausible circumstances in which specific populations potentially have been exposed to doses of ionizing radiation that could cause direct clinical effects within days or weeks, but where there is no clear knowledge as to the, magnitude of the exposure to individuals. Also, while it is likely that many of the exposed individuals will not have received clinically significant doses of radiation, others in the immediate vicinity may have been exposed to potentially life-threatening doses. It is therefore both appropriate and necessary to differentiate among persons and exposure doses sufficiently in order to classify individuals into subclasses for treatment and advice.
In addition, a rapid assessment of radiation doses received by victims is critical for accurate decision-making with respect to post-exposure treatment of exposure victims. It is generally appreciated that, for all but the highest exposure doses which cause prompt biological effects, a unique and challenging aspect of radiological injury is the delayed onset of clinical symptoms following exposure. In this regard, a common problem associated with relatively low to intermediate range exposure doses is that effective decisions regarding further action and/or treatment following victim exposure may be compromised by the lack of information and uncertainty of the dose quantity the victim received. For example, decisions concerning whether to evacuate an area or to return to duty may be difficult in the hours and days immediately following exposure if there is little or inadequate information regarding the ionizing radiation exposure dose.
In response to the need to plan for potential exposure of a large population to harmful radiation, minimal requirements have been established (e.g., by NATO and U.S. military) calling for accurate post-exposure radiation dose assessments for individuals exposed to radioactive contamination [see “Army Specific Military Requirements for Nuclear Weapons and Radiation Effects Information,” FY01/02, 19 Jan. 2000: SMR 3.1.2a, priority 2, and draft NATO Standardization Agreement 2474 on recording of radiation doses for NATO forces, these documents being expressly incorporated by reference herein]. However, the conventional solutions proposed to date for assessing post-exposure doses have not resulted in generally practical and effective techniques.
The Conventional Approach for After-the-Fact Assessment of Radiation Exposure
Potentially, an after-the-fact assessment could be made from biological or physical changes. However, there are very few biological methods truly available for this purpose because of the immediate results of irradiation in-vivo. Even in high exposure dose instances, only a few persons exhibit biological manifestations. The one approach that has been widely used, the measurement of changes in the blood, is non-specific and time-consuming. After exposure, the number of circulating lymphocytes in the blood will decrease, but this manifestation cannot be used to provide a quantitative estimate of exposure dose. Also, certain changes in the chromosomes can be assessed, but this alternative procedure is time-consuming, is technically difficult, and is at best semi-quantitative.
There is one traditional method based on physical changes which is conventionally known and used for assessing radiation exposure. It involves electron paramagnetic resonance (or “EPR”) spectroscopy techniques [which are also known as electron spin resonance (“ESR”)] to assess exposure to ionizing radiation. These techniques measure long-lasting changes in a victim's hard tissues (e.g., teeth and bones) that result from radiation exposure.
Ionizing radiation generates large numbers of unpaired electron species. While most of these react immediately and disappear, in some materials in which diffusion is limited, the unpaired electrons can persist for long periods of time [Brady, J. M., Norman O. Aarestad and Harold M. Swartz (1968), “In Vivo dosimetry by electron spin resonance spectroscopy,” Health Physics, 15:43–47]. This phenomenon has been recognized to occur in bone and teeth for more than 50 years. It was shown to be a feasible method for retrospective dosimetry and subsequently has been used widely for dosimetry in isolated teeth and bones. Teeth are especially attractive because the signal intensity is stronger in them, because of the higher amount of enamel.
Conventional EPR techniques are based on isolated teeth and bones. They require the use of high magnetic field, and therefore employ large magnets and bulky supporting equipment which are suitable only for in-vitro laboratory evaluation. Typically, the EPR technique uses a magnetic field to establish different energy levels for unpaired electrons in hard tissue, which are the result of radiation exposure and which therefore have a net magnetic moment because of electron spin. A radio-frequency (i.e., microwave) electromagnetic field then is applied to the previously exposed hard tissues via a resonator structure to obtain electron transitions between the different energy levels, as established by the magnetic field. A radiation dose then may be estimated based on the received signal intensity. Modulation of the magnetic field additionally may be employed to enhance the sensitivity of electron energy measurements.
Most dosimetry studies based on teeth and reported in the scientific literature have been carried out at conventional EPR frequencies (e.g., 9 GHz) for higher sensitivity and under conditions where some removal of aqueous components is possible [See for example, Harold M. Swartz, Robert P. Molenda and Robert T. Lofberg (1968), “Long-lived radiation-induced electron spin resonances in an aqueous biological system,” Biochem. Biophysical Research Communications, 21:61–65]. Using this approach, it has been possible to measure doses in the range of centiGray (cGy) values in isolated teeth. While such data are useful for many purposes, this approach cannot meet in-vivo needs, because it usually would not be feasible to remove teeth from the population to be screened.
Many conventionally known EPR spectroscopy techniques used in connection with an assessment of radiation exposure are evaluated and discussed in detail within the scientific literature. Some representative publications include the following, each of which is expressly incorporated herein by reference: Harold M. Swartz, Robert P. Molenda and Robert T. Lofberg (1968), “Long-lived radiation-induced electron spin resonances in an aqueous biological system,” Biochem. Biophysical Research Communications, 21:61–65; Brady, J. M., Norman O. Aarestad and Harold M. Swartz (1968), “In Vivo dosimetry by electron spin resonance spectroscopy,” Health Physics, 15:43–47; Ikeya M. and Ishii H. (1989), “Atomic bomb and accident dosimetry with ESR: Natural rocks and human tooth in-vivo spectrometer,” Appl. Radiat. Isotop.m 40:1021–1027; M. Miyake, K. J. Liu, T. Walczak, and H. M. Swartz, “In Vivo EPR Dosimetry of Accidental Exposures to Radiation: Experimental Results Indicating the Feasibility of Practical Use in Human Subjects,” Appl. Rad. & Isotopes 52:1031–1038 (2000); Yamanaka C., Ikeya M. and Hara H. (1993), “ESR cavities for in vivo dosimetry of tooth enamel,” Appl. Radiat. Isotope., 44: 77–80; Ikeya M. and Miki T. (1980), “Electron spin resonance dating of animal and human bones,” Science, 207: 977–979; Polyakov V. Haskell E., Kenner G., Huett G., and Hayes R. (1995), “Effect of mechanically induced background signal on EPR on dosimetry of tooth enamel,” Radiat. Measure., 24: 249–254; Pass B. and Aldrich J. E. (1985), “Dental enamel as an in vivo radiation dosimeter,” Med. Phys. 12:305–307; Hoshi M., Sawada S., Ikeya M. and Miki T. (1985), “ESR dosimetry for A-bomb survivors,” ESR dating and Dosimetry, 407–414 Ionics, Tokyo; Ishii H., Ikeya M. and Okano S. (1990), “ESR dosimetry of teeth of residents close to the Chernobyl reactor accident,” J. Nucl. Sci. Tech. 27:1153–1155; and Romanyukha A. A., Regulla D., Vasilenko E. and Wieser A., (1994), “South Ural nuclear workers: Comparison of individual doses from retrospective EPR dosimetry personal monitoring,” Appl. Radiat. Isot., 45:1195–1199.
It will be noted and recognized that among the publications cited above are some which employ the term “in-vivo” in their title or content; however, none of these report results in which the empirical measurements were made in-vivo using living human subjects. The true informational value of these printed publications must therefore be very carefully and critically considered.
In addition, oxygen monitoring—a related EPR technology—is described in the patent literature. This is illustrated by the apparatus and methodology for determining oxygen in biological systems disclosed by U.S. Pat. Nos. 5,833,601 and 5,494,000 respectively.
Also, a number of scientific publications describe magnetic design methods in a variety of forms. These scientific publications are represented by: Hawksworth, D., New Magnet Design for MR, Mag. Res. in Medicine 17, 27–32 (1991). For magnetic design see also: Montgomery, D. B., Solenoid Magnet Design, Krieger Publishing Co. Inc, Huntingdon, N.Y. 1980.
In addition, a number of publications are directed to methods of constrained or non-constrained optimization without any direct mention of magnets as such. These include: Brent, R. P., Algorithms for Minimization without Derivatives, Prentice-Hall, Englewood, N.J.; Bertsekis, D. P., 1982, Constrained Optimization and Lagrange Multiplier Methods, Academic Press; and Powell, M. J. D., 1964, An efficient Method for Finding the Minimum of a Function of Several Variables without Calculating Derivatives, Comp. J., 7, 155–162 (1964).
Lastly, the patent literature provides a variety of useful magnet assemblies. These are merely illustrated by U.S. Pat. Nos. 4,701,736; 4,985,679; and 6,208,142 respectively.
Accordingly, for purposes of an easier understanding and a better appreciation of the present invention, the text of each individual scientific publication and each issued U.S. patent identified above is expressly incorporated by reference herein.
Present Obstacles and Challenges
A number of substantive technical obstacles and major scientific challenges presently stand in the way of meaningful improvements and effective advances in this field in order to make sensitive and accurate measurements in-vivo in humans. Among the long-standing and well recognized problems are the following.
The conventionally known EPR spectrometer is a bulky, stationary apparatus which is useful only in the analytical laboratory environment and requires careful operation by highly skilled technicians. Among the EPR spectrometer adopted for in-vitro analyses of hard human tissues such as teeth, none of them is portable or transportable and none of them can be operated by minimally trained individuals.
The usual size and weight of a conventional magnet makes it difficult to meet the logistical requirements for rapid measurements and transportability. Also, the power requirements for the conventional, higher field, magnet typically make the idea of a portable magnet nearly impossible.
The resonator is another technical challenge, because of the irregular shape of the teeth. The EPR signal is located principally in the enamel of the teeth, so the optimization of the sensitive volume of the resonator includes probing the maximum amount of enamel. Typically, a good sampling of the enamel requires the testing of one to several teeth.
A fourth area of technical challenge is the need to optimize a weak signal, which includes eliminating the overlapping background signal. With isolated teeth, the in-vitro dose-response for the tooth in question can be determined with the use of added known doses, with extrapolation back to the original dose. This option, of course, cannot be used with teeth in vivo.
Clearly therefore, the development of a portable apparatus and methods able to detect and accurately measure post-exposure doses of ionizing radiation in the teeth of living subjects is viewed as an unforeseeable and unpredictable event by persons technically skilled in this field. Equally important, were such a portable apparatus and detection method brought into functional existence on a practical use basis, such a development would be recognized as being a major advance of unusual benefit and value. Such after-the-fact measurements could also then be utilized for quality control of therapeutic radiation treatments.